PMID- 23041626
OWN - NLM
STAT- MEDLINE
DCOM- 20130115
LR  - 20220224
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 122
IP  - 11
DP  - 2012 Nov
TI  - Progranulin deficiency promotes neuroinflammation and neuron loss following 
      toxin-induced injury.
PG  - 3955-9
LID - 63113 [pii]
LID - 10.1172/JCI63113 [doi]
AB  - Progranulin (PGRN) is a widely expressed secreted protein that is linked to 
      inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of 
      frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration 
      is unknown. Here we show that loss of PGRN results in increased neuron loss in 
      response to injury in the CNS. When exposed acutely to 
      1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN 
      (Grn(-)/(-)) showed more neuron loss and increased microgliosis compared with 
      wild-type mice. The exacerbated neuron loss was due not to selective 
      vulnerability of Grn(-)/(-) neurons to MPTP, but rather to an increased microglial 
      inflammatory response. Consistent with this, conditional mutants lacking PGRN in 
      microglia exhibited MPTP-induced phenotypes similar to Grn(-)/(-) mice. Selective 
      depletion of PGRN from microglia in mixed cortical cultures resulted in increased 
      death of wild-type neurons in the absence of injury. Furthermore, Grn(-)/(-) 
      microglia treated with LPS/IFN-gamma exhibited an amplified inflammatory response, 
      and conditioned media from these microglia promoted death of cultured neurons. 
      Our results indicate that PGRN deficiency leads to dysregulated microglial 
      activation and thereby contributes to increased neuron loss with injury. These 
      findings suggest that PGRN deficiency may cause increased neuron loss in other 
      forms of CNS injury accompanied by neuroinflammation.
FAU - Martens, Lauren Herl
AU  - Martens LH
AD  - Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, 
      USA.
FAU - Zhang, Jiasheng
AU  - Zhang J
FAU - Barmada, Sami J
AU  - Barmada SJ
FAU - Zhou, Ping
AU  - Zhou P
FAU - Kamiya, Sherry
AU  - Kamiya S
FAU - Sun, Binggui
AU  - Sun B
FAU - Min, Sang-Won
AU  - Min SW
FAU - Gan, Li
AU  - Gan L
FAU - Finkbeiner, Steven
AU  - Finkbeiner S
FAU - Huang, Eric J
AU  - Huang EJ
FAU - Farese, Robert V Jr
AU  - Farese RV Jr
LA  - eng
GR  - P50 AG023501/AG/NIA NIH HHS/United States
GR  - I01 BX001108/BX/BLRD VA/United States
GR  - GMO 100909/PHS HHS/
GR  - RR18928/RR/NCRR NIH HHS/United States
GR  - K08 NS072233/NS/NINDS NIH HHS/United States
GR  - P01 AG022074/AG/NIA NIH HHS/United States
GR  - F31 AG034793/AG/NIA NIH HHS/United States
GR  - C06 RR018928/RR/NCRR NIH HHS/United States
GR  - R01 AG036884/AG/NIA NIH HHS/United States
GR  - R01 NS039074/NS/NINDS NIH HHS/United States
GR  - R01 AG030207/AG/NIA NIH HHS/United States
GR  - K26 OD010927/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20121008
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Granulins)
RN  - 0 (Grn protein, mouse)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neurotoxins)
RN  - 0 (Progranulins)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
SB  - IM
EIN - J Clin Invest. 2022 Jan 4;132(1):. PMID: 34981791
MH  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*adverse effects/pharmacology
MH  - Animals
MH  - Cell Death/drug effects/genetics
MH  - Cells, Cultured
MH  - Cerebral Cortex/metabolism/pathology
MH  - Frontotemporal Dementia/genetics/metabolism/pathology
MH  - Granulins
MH  - Humans
MH  - Inflammation/chemically induced/genetics/metabolism/pathology
MH  - Intercellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Interferon-gamma/pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - MPTP Poisoning/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Microglia/*metabolism/pathology
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Neurons/*metabolism/pathology
MH  - Neurotoxins/*adverse effects/pharmacology
MH  - Progranulins
PMC - PMC3484443
EDAT- 2012/10/09 06:00
MHDA- 2013/01/16 06:00
PMCR- 2012/10/08
CRDT- 2012/10/09 06:00
PHST- 2012/01/30 00:00 [received]
PHST- 2012/08/17 00:00 [accepted]
PHST- 2012/10/09 06:00 [entrez]
PHST- 2012/10/09 06:00 [pubmed]
PHST- 2013/01/16 06:00 [medline]
PHST- 2012/10/08 00:00 [pmc-release]
AID - 63113 [pii]
AID - 10.1172/JCI63113 [doi]
PST - ppublish
SO  - J Clin Invest. 2012 Nov;122(11):3955-9. doi: 10.1172/JCI63113. Epub 2012 Oct 8.